African Americans (AA) are on average 4 times more likely to suffer from chronic kidney disease (CKD) than European Americans. Recent studies have identified that APOL1 genetic risk variants are associated with higher risker for developing progressive CKD, and especially among those infected with HIV. The risk is up to 89 fold higher for those HIV individuals carrying with two APOL1 risk alleles compared to low risk carriers. However, the majority of African Americans who carry APOL1 risk alleles do not develop CKD, suggesting additional factors are required for CKD development. Soluble urokinase receptor (suPAR) has also been identified as risk factor for CKD including patients with HIV. Novel studies show that APOL1 and suPAR biochemically interact and clinically, AA patients with both risk factors show the steepest yearly eGFR decline. This translational proposal seeks to investigate the risk of combined impact of genetic (APOL1) and environmental (suPAR) factors for development and progression of CKD. The proposal analyzes APOL1 risk in the setting of HIV infection, which is associated with high levels of suPAR that may be attenuated in those treated anti-retroviral therapy. We propose an innovative study including HIV infected individuals from a well-established clinic sub-Saharan- Africa (SSA) with high prevalence of APOL1 risk alleles to unravel insights into the unique relationship of suPAR and APOL1. This proposal provides a large population to understand gene-environment risk with adequate power, in a clinic with standardized clinical protocols and free access to health care and medications, and lastly a complimentary H3 Africa Kidney Network to validate findings. With these unique study attributes, we hypothesize that suPAR and APOL1 gene mutation alone or in combination are driving forces in the development and progression of CKD in HIV. Thus, in this proposed research program, we will conduct the following: Aim 1, Determine the demographic, clinical and biochemical factors associated with suPAR levels in 1000 HIV individuals before and after ART; Aim 2, Evaluate the association of suPAR level and APOL 1 mutation with CKD prevalence and proteinuria among 5,000 HIV; and Aim 3, Determine the longitudinal association of APOL1 risk and repeated suPAR levels with incidence and progression of among study of 3000 HIV individuals on ART. We will also validate the findings in the H3 Africa HIV-CKD cohort. In sum, this research program provides important information on the factors contributing to elevated suPAR levels, the association with CKD and also longitudinal association with repeated measures. These novel findings will be the basis for preventive and treatment strategies to combat APOL1-CKD.